The present invention relates generally to protection against herpes simplex virus (HSV) infection. While the invention is subject to a wide range of applications, it relates especially to a vaccine suited for vaccination of animals and humans against herpes simplex virus 2 (HSV-2) and herpes simplex virus 1 (HSV-1) and the prevention of associated illness such as genital herpes. In addition, the invention provides methods of preparing a vaccine against HSV-2 and HSV-1 infections and methods of use thereof.
The disease burden associated with HSV-2 infection, an important cause of genital herpes worldwide, is high and presents an additional threat due to its association with an increased risk of human immunodeficiency virus (HIV) acquisition and transmission (Xu F et al. 2006. JAMA 296(8), 964-973; Freeman E E et al. 2006. AIDS 20(1), 73-83; Cowan F & Pettifor A. 2009. Curr Opin HIV AIDS 4(4), 288-293). Globally, HSV-2 is a major health threat with 16% of the US population infected by age 30 and 50-90% of the population in sub-Saharan Africa (Cowan F & Pettifor A. 2009. Curr Opin HIV AIDS 4(4), 288-293; Xu F et al. 2010. Morbidity and Mortality Weekly Report, CDC 59(15), 456-459; Bradley H et al. 2014. J Infect Dis 209(3):325-33). Recent reports emphasize the importance of HSV-1 as an important etiologic agent of genital herpes particularly in the US and other developed countries (Ryder N et al. 2009. Sex Transm Infect 85(6):416-9; Pereira V S et al. 2012. Eur J Obstet Gynecol Reprod Biol 161(2):190-3; Bernstein D I et al. 2013. Clin Infect Dis 56(3):344-51). Seroprevalence of HSV-1 among 14-49-year-old in the US reached 53.9% in 2005-2010 (Bradley H et al. 2014. J Infect Dis 209(3):325-33). No effective vaccine is available to prevent the acquisition or spread of either HSV serotype.
Vaccine efforts focus on subunit vaccines that include viral envelope glycoproteins alone or in combination with other structural and non-structural viral proteins, replication-defective viruses, and vectored and peptide-based vaccines (Stanberry L R. 2004. Herpes 11 Suppl 3, 161A-169A; Koelle D M & Corey L. 2008. Annu Rev Med 59, 381-395; Halford W P. 2014. Expert Rev Vaccines 13(6):691-710). Subunit vaccines based on the HSV-2 glycoprotein D (gD-2) were advanced to clinical trials based on efficacy in small animal models (Bourne N et al. 2003. J Infect Dis 187(4), 542-549; Bourne N et al. 2005. J Infect Dis 192(12), 2117-2123; Hoshino Y et al. 2005. J Virol 79(1):410-8). However, the results of the most recent gD-2 subunit vaccine clinical trials were unexpected (Stanberry L R. 2004. Herpes 11 Suppl 3, 161A-169A; Belshe R B et al. 2012. N Engl J Med 366(1), 34-43). Two double-blind randomized Phase 2 studies of the gD-2 vaccine Simplirix™, containing aluminum salt and monophosphoryl lipid A (MPL) adjuvants (gD/AS04), found 73% and 74% efficacy against genital disease in HSV-discordant couples in women who were seronegative for both HSV-1 and HSV-2, but no protection in women who were seropositive for HSV-1 at enrollment or in men (Stanberry L R et al. 2002. N Engl J Med 347(21), 1652-1661). The subsequent Phase 3 trial, which was conducted among 8,323 women 18 to 30 years of age who were seronegative for both HSV-1 and HSV-2 at enrollment, revealed that gD/AS04 vaccine was not effective against HSV-2 genital herpes disease despite inducing HSV-specific enzyme-linked immunosorbent assay (ELISA) and neutralizing antibodies (Belshe R B et al. 2012. N Engl J Med 366(1), 34-43). However, the vaccine did provide 58% (95% CI 12 to 80) protection against HSV-1 genital disease (Belshe R B et al. 2012. N Engl J Med 366(1), 34-43). These findings highlight the need for new preclinical models that may prove more predictive of vaccine trial outcomes.
Genital herpes caused by HSV-1 or HSV-2 is a debilitating disease that also predisposes individuals to acquisition of HIV. In spite of the high health burden of genital herpes, there is still no effective vaccine or intervention against the disease. The significant gap in knowledge on genital herpes pathogenesis has been further highlighted by the recent failure of HSV-2 vaccine Simplirix™ (gD/AS04) to protect humans against HSV-2 and the surprising finding that the vaccine protected against HSV-1 genital herpes instead. The failure of HSV-2 vaccine Simplirix™ (gD/AS04) emphasizes the need for alternative vaccine strategies and the identification of new correlates of protection against genital herpes. Thus, there remains a need for safe and effective approaches to protect animals and humans against HSV-2 and HSV-1, and their associated diseases such as genital herpes. In particular, there remains a need for specific vaccines to prevent HSV-2 and HSV-1 infections, and for therapeutic approaches to prevent illnesses associated with HSV-2 and HSV-1 infections. The data obtained in previous studies suggested that efficient protection against genital herpes is associated with a polyvalent antibody response against antigens present in extracts of HSV-infected Vero cells (Boukhvalova et al. 2015. J Virol 89(19), 9825-40).